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| United States Patent |
5,262,537
|
|
Huang
, et al.
|
November 16, 1993
|
Derivatives of 4,5,6,7-tetrahydroimidazo-[4,5-c]pyridinyl-6-carboxylic
acid
Abstract
This invention pertains to a method for treating a condition of nausea and
vomiting in a mammal which comprises administering a therapeutically
effective amount of a
4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid derivative
represented by the formula:
##STR1##
wherein R.sub.1 and R.sub.2 are hydrogen or lower-alkyl; R.sub.3 is
selected from the group consisting of hydrogen, lower-alkyl, nitro, amino,
cyano, and alkylmercapto; R.sub.4 and R.sub.5 are selected from the group
consisting of hydrogen, lower-alkyl, aryl, and aryl lower-alkyl, or
R.sub.4 and R.sub.5 together with the carbon atom to which they are
attached form a 5- or 6-member saturated hydrocarbon ring; R.sub.6 is
selected from the group consisting of hydrogen, lower-alkyl, aryl
lower-alkyl, formyl, lower-alkyl carbonyl, and aryl carbonyl; R.sub.7 is
selected from the group consisting of phenyl, thienyl, indolyl, indazolyl,
benzo[b]furanyl, benzo[b]thiophenyl, and R.sub.8 R.sub.9 --N--; R.sub.8 is
selected from the group consisting of 8-[1,2,3,4,-tetrahydroquinolinyl],
pyridinyl, 3-quinolinyl, 2-naphthalinyl, 2-thiazolyl, 2-benzothiazolyl,
4-[2,1,3]benzothiadiazolyl, 2-(4,5,6,7-tetrahydrobenzo)thiazolyl,
7-(2,2-dimethyl-2,3-dihydrobenzo)furanyl, and phenyl; R.sub.9 is hydrogen
or lower-alkyl; R.sub.8 R.sub.9 --N-- is selected from the group
consisting of 1-indolinyl, 1-(3,3-dimethylindolinyl), and
1-(1,2,3,4-tetrahydroquinolinyl); wherein the groups represented by
R.sub.7 other than R.sub.8 R.sub.9 N-- may be unsubstituted or substituted
with one or more substituents selected from the group consisting of
lower-alkyl, lower-alkoxy, di-lower-alkylamino, and aryloxy, and the
groups represented by R.sub.8 and the radical R.sub.8 R.sub.9 N-- may have
one or more substituents selected from the group consisting of hydroxy,
halogen, lower-alkyl, lower-alkoxy, amino, mono- or di-lower-alkylamino,
lower-alkyl carbonyl, lower-alkoxy carbonyl, and aryloxy; wherein each
aryloxy group may be unsubstituted or substituted with substituents
independently selected from the group consisting of lower-alkyl,
lower-alkoxy, halogen, and trifluoromethyl with the proviso that, when
R.sub.8 is phenyl, said phenyl group contains at least one substituent.
| Inventors:
|
Huang; Bao-Shan (Edison, NJ);
Feng; Danging D. (Branchburg Township, Somerset County, NJ);
Gall; Martin (Morris Township, Morris County, NJ);
Evans; Suzanne M. (Springfield, NJ);
Paradkar; Vidyadhar M. (Basking Ridge, NJ);
Nair; Raghunathan V. (Basking Ridge, NJ);
Latham; Tamara B. (North Plainfield, NJ)
|
| Assignee:
|
Anaquest, Inc. (Liberty Corner, NJ)
|
| Appl. No.:
|
033522 |
| Filed:
|
March 19, 1993 |
| Current U.S. Class: |
546/118; 546/15 |
| Intern'l Class: |
A61K 031/445; A61K 031/415; C07D 471/04; C07D 471/10 |
| Field of Search: |
546/15,118
514/278,303
|
References Cited
U.S. Patent Documents
| 4977175 | Dec., 1990 | Ohta et al. | 514/394.
|
Primary Examiner: Ivy; C. Warren
Assistant Examiner: Mach; D. Margaret M.
Attorney, Agent or Firm: Swope; R. Hain, Cassett; Larry R.
Claims
We claim:
1. A 4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid derivative
represented by the formula:
##STR12##
including optically active isomeric forms, and the pharmaceutically
acceptable acid addition salts thereof, wherein:
R.sub.1 and R.sub.2 are individually hydrogen or lower-alkyl;
R.sub.3 is selected from the group consisting of hydrogen, lower-alkyl,
nitro, amino, cyano, and alkylmercapto;
R.sub.4 and R.sub.5 are independently selected from the group consisting of
hydrogen, lower-alkyl, aryl, and aryl lower-alkyl, or R.sub.4 and R.sub.5
together with the carbon atom to which they are attached form a 5- or
6-member saturated hydrocarbon ring;
R.sub.6 is selected from the group consisting of hydrogen, lower-alkyl,
aryl lower-alkyl, formyl, lower-alkyl carbonyl, and aryl carbonyl;
R.sub.7 is selected from the group consisting of phenyl, thienyl, indolyl,
indazolyl, benzo[b]furanyl, benzo[b]thiophenyl, and R.sub.8 R.sub.9 --N--;
and
R.sub.8 is selected from the group consisting of
8-[1,2,3,4-tetrahydroquinolinyl], pyridinyl, 3-quinolinyl, 2-naphthalinyl,
2-thiazolyl, 2-benzothiazolyl, 4-[2,1,3]benzothiadiazolyl,
2-(4,5,6,7-tetrahydrobenzo)thiazolyl,
7-(2,2-dimethyl-2,3-dihydrobenzo)furanyl, and phenyl;
R.sub.9 is hydrogen or lower-alkyl;
R.sub.8 R.sub.9 --N-- is a radical selected from the group consisting of
1-indolinyl, 1-(3,3-dimethylindolinyl), and
1-(1,2,3,4-tetrahydroquinolinyl); wherein the groups represented by
R.sub.7 other than R.sub.8 R.sub.9 N-- may be unsubstituted or substituted
with one or more substituents selected from the group consisting of
lower-alkyl, lower-alkoxy, di-lower-alkylamino, and aryloxy, and the
groups represented by R.sub.8 and the radical R.sub.8 R.sub.9 N-- may have
one or more substituents selected from the group consisting of hydroxy,
halogen, lower-alkyl, lower-alkoxy, amino, mono-or di-lower-alkylamino,
lower-alkyl carbonyl, lower-alkoxy carbonyl, and aryloxy, wherein each
aryloxy group may be unsubstituted or substituted with one or more
substituents independently selected from the group consisting of
lower-alkyl, lower-alkoxy, halogen, and trifluoromethyl with the proviso
that, when R.sub.8 is phenyl, said phenyl group contains at least one
substituent;
wherein the symbol * represents an asymmetric carbon atom at position 6
which may be in the R or S configuration, and each lower-alkyl group
contains from 1 to 6 carbon atoms.
2. The compound according to claim 1, wherein R.sub.1, R.sub.2, R.sub.4,
and R.sub.5 are individually hydrogen or methyl.
3. The compound according to claim 1, wherein R.sub.3 is selected from the
group consisting of hydrogen, lower-alkyl, nitro, and amino.
4. The compound according to claim 1, wherein R.sub.1, R.sub.2, and R.sub.3
are hydrogen.
5. The compound according to claim 1, wherein R.sub.6 is hydrogen or
lower-alkyl.
6. The compound according to claim 1, which comprises
(R)-6-(2-benzothiazolylaminocarbonyl)-5-methyl-4,5,6,7-tetrahydroimidazo[4
,5-c]pyridine, and the pharmaceutically acceptable addition salts thereof.
7. The compound according to claim 1, wherein R.sub.7 is R.sub.8 R.sub.9
--N--, R.sub.8 is phenyl containing one or more substituents independently
selected from the group consisting of hydroxy, aryloxy, lower-alkyl
carbonyl, and lower-alkoxy carbonyl, and R.sub.9 is hydrogen.
8. The compound according to claim 7, which comprises
(S)-6-(2-acetylphenylaminocarbonyl)-5-methyl-4,5,6,7-tetrahydroimidazo[4,5
-c]pyridine, and the pharmaceutically acceptable addition salts thereof.
9. The compound according to claim 7, which comprises
(S)-6-(2-phenoxyphenylaminocarbonyl)-5-methyl-4,5,6,7-tetrahydroimidazo[4,
5-c]pyridine, and the pharmaceutically acceptable addition salts thereof.
10. The compound according to claim 1, wherein R.sub.7 is selected from the
group consisting of phenyl, thienyl, indolyl, indazolyl, benzo[b]furanyl,
and benzo[b]thiophenyl.
11. A pharmaceutical composition for treating a nausea and vomiting
condition in a mammal which comprises a pharmaceutically acceptable
carrier and a therapeutically effective amount of a
4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid derivative
represented by the formula:
##STR13##
including optically active isomeric forms, and the pharmaceutically
acceptable acid addition salts thereof, wherein:
R.sub.1 and R.sub.2 are individually hydrogen or lower-alkyl;
R.sub.3 is selected from the group consisting of hydrogen, lower-alkyl,
nitro, amino, cyano, and alkylmercapto;
R.sub.4 and R.sub.5 are independently selected from the group consisting of
hydrogen, lower-alkyl, aryl, and aryl lower-alkyl, or R.sub.4 and R.sub.5
together with the carbon atom to which they are attached form a 5- or
6-member saturated hydrocarbon ring;
R.sub.6 is selected from the group consisting of hydrogen, lower-alkyl,
aryl lower-alkyl, formyl, lower-alkyl carbonyl, and aryl carbonyl;
R.sub.7 is selected from the group consisting of phenyl, thienyl, indolyl,
indazolyl, benzo[b]furanyl, benzo[b]thiophenyl, and R.sub.8 R.sub.9 --N--;
and
R.sub.8 is selected from the group consisting of
8-[1,2,3,4,-tetrahydroquinolinyl], pyridinyl, 3-quinolinyl,
2-naphthalinyl, 2-thiazolyl, 2-benzothiazolyl, 4-[2,1,3]benzothiadiazolyl,
2-(4,5,6,7-tetrahydrobenzo)thiazolyl,
7-(2,2-dimethyl-2,3-dihydrobenzo)furanyl, and phenyl;
R.sub.9 is hydrogen or lower-alkyl;
R.sub.8 R.sub.9 --N-- is a radical selected from the group consisting of
1-indolinyl, 1-(3,3-dimethylindolinyl), and
1-(1,2,3,4-tetrahydroquinolinyl); wherein the groups represented by
R.sub.7 other than R.sub.8 R.sub.9 N-- may be unsubstituted or substituted
with one or more substituents selected from the group consisting of
lower-alkyl, lower-alkoxy, di-lower-alkylamino, and aryloxy, and the
groups represented by R.sub.8 and the radical R.sub.8 R.sub.9 N-- may have
one or more substituents selected from the group consisting of hydroxy,
halogen, lower-alkyl, lower-alkoxy, amino, mono-or di-lower-alkylamino,
lower-alkyl carbonyl, lower-alkoxy carbonyl, and aryloxy, wherein each
aryloxy group may be unsubstituted or substituted with one or more
substituents independently selected from the group consisting of
lower-alkyl, lower-alkoxy, halogen, and trifluoromethyl with the proviso
that, when R.sub.8 is phenyl, said phenyl group contains at least one
substituent;
wherein the symbol * represents an asymmetric carbon atom at position 6
which may be in the R or S configuration, and each lower-alkyl group
contains from 1 to 6 carbon atoms.
12. A method for treating a condition of nausea and vomiting in a mammal
which comprises administering to the mammal an amount, therapeutically
effective to relieve the condition, of a
4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid derivative
represented by the formula:
##STR14##
including optically active isomeric forms, and the pharmaceutically
acceptable acid addition salts thereof, wherein:
R.sub.1 and R.sub.2 are individually hydrogen or lower-alkyl;
R.sub.3 is selected from the group consisting of hydrogen, lower-alkyl,
nitro, amino, cyano, and alkylmercapto;
R.sub.4 and R.sub.5 are independently selected from the group consisting of
hydrogen, lower-alkyl, aryl, and aryl lower-alkyl, or R.sub.4 and R.sub.5
together with the carbon atom to which they are attached form a 5- or
6-member saturated hydrocarbon ring;
R.sub.6 is selected from the group consisting of hydrogen, lower-alkyl,
aryl lower-alkyl, formyl, lower-alkyl carbonyl, and aryl carbonyl;
R.sub.7 is selected from the group consisting of phenyl, thienyl, indolyl,
indazolyl, benzo[b]furanyl, benzo[b]thiophenyl, and R.sub.8 R.sub.9 --N--;
and
R.sub.8 is selected from the group consisting of
8-[1,2,3,4,-tetrahydroquinolinyl], pyridinyl, 3-quinolinyl,
2-naphthalinyl, 2-thiazolyl, 2-benzothiazolyl, 4-[2,1,3]benzothiadiazolyl,
2-(4,5,6,7-tetrahydrobenzo)thiazolyl,
7-(2,2-dimethyl-2,3-dihydrobenzo)furanyl, and phenyl;
R.sub.9 is hydrogen or lower-alkyl;
R.sub.8 R.sub.9 --N-- is a radical selected from the group consisting of
1-indolinyl, 1-(3,3-dimethylindolinyl), and
1-(1,2,3,4-tetrahydroquinolinyl); wherein the groups represented by
R.sub.7 other than R.sub.8 R.sub.9 N-- may be unsubstituted or substituted
with one or more substituents selected from the group consisting of
lower-alkyl, lower-alkoxy, di-lower-alkylamino, and aryloxy, and the
groups represented by R.sub.8 and the radical R.sub.8 R.sub.9 N-- may have
one or more substituents selected from the group consisting of hydroxy,
halogen, lower-alkyl, lower-alkoxy, amino, mono- or di-lower-alkylamino,
lower-alkyl carbonyl, lower-alkoxy carbonyl, and aryloxy, wherein each
aryloxy group may be unsubstituted or substituted with one or more
substituents independently selected from the group consisting of
lower-alkyl, lower-alkoxy, halogen, and trifluoromethyl with the proviso
that, when R.sub.8 is phenyl, said phenyl group contains at least one
substituent;
wherein the symbol * represents an asymmetric carbon atom at position 6
which may be in the R or S configuration, and each lower-alkyl group
contains from 1 to 6 carbon atoms.
13. The method according to claim 12, wherein R.sub.1, R.sub.2, R.sub.4,
and R.sub.5 are individually hydrogen or methyl.
14. The method according to claim 12, wherein R.sub.3 is selected from the
group consisting of hydrogen, lower-alkyl, nitro, and amino.
15. The method according to claim 12, wherein R.sub.1, R.sub.2, and R.sub.3
are hydrogen.
16. The method according to claim 12, wherein R.sub.6 is hydrogen or
lower-alkyl.
17. The method according to claim 12, wherein said compound of formula (1)
comprises
(R)-6-(2-benzothiazolyl)aminocarbonyl-5-methyl-4,5,6,7-tetrahydroimidazo[4
,5-c]pyridine, and the pharmaceutically acceptable addition salts thereof.
18. The method according to claim 12, wherein R.sub.7 is R.sub.8 R.sub.9
--N--, R.sub.8 is phenyl containing one or more substituents independently
selected from the group consisting of hydroxy, lower-alkyl carbonyl, and
lower-alkoxy carbonyl, and R.sub.9 is hydrogen.
19. The method according to claim 18, wherein said compound of formula (1)
comprises
(S)-6-(2-acetylphenyl)aminocarbonyl-5-methyl-4,5,6,7-tetrahydroimidazo[4,5
-c]pyridine, and the pharmaceutically acceptable addition salts thereof.
20. The method according to claim 18, wherein said compound of formula (1)
comprises
(S)-6-(2-phenoxy-phenyl)aminocarbonyl-5-methyl-4,5,6,7-tetrahydroimidazo[4
,5-c]pyridine, and the pharmaceutically acceptable addition salts thereof.
21. The method according to claim 12, wherein R.sub.7 is selected from the
group consisting of phenyl, thienyl, indolyl, indazolyl, benzo[b]furanyl,
and benzo[b]thiophenyl.
Description
FIELD OF THE INVENTION
This invention relates to derivatives of novel
4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid useful as
potent and selective anti-emetic or anti-nausea agents, or both, for
pre-operative, intra-operative, and post-operative use.
BACKGROUND OF THE INVENTION
Nausea and vomiting are a serious complication of surgery and certain areas
of chemotherapy, particularly cancer treatment. Historically, dopamine
receptor antagonists, such as droperidol or prochlorperazine, have been
used to treat nausea and vomiting. These agents, however, tend to produce
unwanted side effects such as prolactin release and sedation.
Recently, a new class of agents, characterized by their antagonism of
serotonin at the 5-HT.sub.3 receptor with little or no D.sub.2 receptor
antagonist properties, has been found to prevent or curtail emetic
episodes caused by irradiation or chemotherapeutic agents such as
cisplatin. These effects were potentiated by coadministration of
dexamethasone. In addition, these 5-HT.sub.3 antagonists are useful in
the treatment of gastric motility, anxiety, migraine, psychiatric
disorders, and memory impairment. Various analogs of these new agents were
found to have effects at a new serotonin receptor which is coupled to
adenylate cyclase, and which has been called the 5HT.sub.4 receptor.
Agents of this latter type are thought to be associated with promotility
and, therefore, have potential utility in treating gastrointestinal
dysfunctions such as reflux oesophagitis and gastric stasis.
United Kingdom patent application no. 2,158,440, discloses certain
4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl carboxylic amide derivatives
useful as antiviral agents.
U.S. Pat. No. 4,977,175, issued to Ohta et al., discloses
4,5,6,7-tetrahydrobenzimidazole derivatives useful as antagonists of
5-HT.sub.3 receptors.
U.S. Pat. No. 4,963,546, issued to North et al., discloses 3-substituted
indole derivatives useful as antagonists of 5-HT.sub.3 receptors.
SUMMARY OF THE INVENTION
This invention pertains to a method for treating a condition, such as
nausea and vomiting mediated through 5-HT.sub.3 receptors alone, or in
combination with other mechanisms, which comprises administering to the
mammal an amount, therapeutically effective to relieve the condition, of a
derivative of 4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid
represented by the formula:
##STR2##
including optically active isomeric forms, and the pharmaceutically
acceptable acid addition salts thereof, wherein:
R.sub.1 and R.sub.2 are hydrogen or lower-alkyl;
R.sub.3 is selected from the group consisting of hydrogen, lower-alkyl,
nitro, amino, cyano, and alkylmercapto;
R.sub.4 and R.sub.5 are independently selected from the group consisting of
hydrogen, lower-alkyl, aryl, and aryl lower-alkyl, or R.sub.4 and R.sub.5
together with the carbon atom to which they are attached form a 5- or
6-member saturated hydrocarbon ring;
R.sub.6 is selected from the group consisting of hydrogen, lower-alkyl,
aryl lower-alkyl, formyl, lower-alkyl carbonyl, and aryl carbonyl;
R.sub.7 is selected from the group consisting of phenyl, thienyl, indolyl,
indazolyl, benzo[b]furanyl, benzo[b]thiophenyl, and R.sub.8 R.sub.9 --N--;
and
R.sub.8 is selected from the group consisting of
8-(1,2,3,4,-tetrahydroquinolinyl), pyridinyl, 3-quinolinyl, 2-naphthyl,
2-thiazolyl, 2-benzothiazolyl, 4-[2,1,3]benzothiadiazolyl,
2-(4,5,6,7-tetrahydrobenzo)thiazolyl,
7-(2,2-dimethyl-2,3-dihydrobenzo)furanyl, and phenyl;
R.sub.9 is hydrogen or lower-alkyl;
R.sub.8 R.sub.9 --N-- is a radical selected from the group consisting of
1-indolinyl, 1-(3,3-dimethylindolinyl), and
1-(1,2,3,4-tetrahydroquinolinyl); wherein the groups represented by
R.sub.7 other than R.sub.8 R.sub.9 N-- may be unsubstituted or substituted
with one or more substituents selected from the group consisting of
lower-alkyl, lower-alkoxy, di-lower-alkylamino, and aryloxy, and the
groups represented by R.sub.8 and the radical R.sub.8 R.sub.9 N-- may have
one or more substituents selected from the group consisting of hydroxy,
halogen, lower-alkyl, lower-alkoxy, amino, mono-or di-lower-alkylamino,
lower-alkyl carbonyl, lower-alkoxy carbonyl, and aryloxy, wherein each
aryloxy group may be unsubstituted or substituted with one or more
substituents independently selected from the group consisting of
lower-alkyl, lower-alkoxy, halogen, and trifluoromethyl;
wherein the symbol * represents an asymmetric carbon atom at position 6
which may be in the R or S configuration, and each lower-alkyl group
contains from 1 to 6 carbon atoms.
This invention also includes novel compounds within the scope of those
represented by formula (I) and methods for their preparation. This
invention relates also to methods for preparing and using the
4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid derivatives
and the pharmaceutical compositions in which they may be employed.
DETAILED DESCRIPTION OF THE INVENTION
The derivatives of 4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic
acid of the present invention block the emetic response induced by
cytotoxic agents such as cisplatin or radiation and are therefore useful
in the treatment of nausea and vomiting generally associated with cancer
therapy. The subject compounds are also useful for treating patients
experiencing post-operative emesis produced by anesthetics and/or adjunct
drugs used in such procedures.
Many of the subject compounds are potent and selective antagonists of the
neuronal 5-HT.sub.3 receptor. However, the most potent of the subject
anti-emetics do not necessarily have the highest affinity to the
5-HT.sub.3 receptor. Therefore, the pharmacology of the subject compounds
is not explainable simply on the basis of current knowledge of the role of
5-HT.sub.3 antagonists in the treatment of nausea and vomiting.
The method of the present invention for treating a condition of nausea and
vomiting in a mammal mediated through 5-HT.sub.3 receptors alone, or in
combination with other mechanisms, comprises administering to the mammal
an amount, therapeutically effective to relieve the condition, of a
4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid compound
represented by the general formula (1):
##STR3##
including optically active isomeric forms, and the pharmaceutically
acceptable acid addition salts thereof. The symbol * represents an
asymmetric carbon atom at position 6 which may be in the R or S
configuration, and preferably is in the S configuration. Groups R.sub.1
through R.sub.7 are defined as set forth below.
In formula (1), R.sub.1 and R.sub.2 are individually hydrogen or
lower-alkyl, preferably, hydrogen or methyl, and more preferably,
hydrogen. R.sub.2 may be attached to the nitrogen atom at position 1 or
position 3 in the imidazole ring.
R.sub.3 is selected from the group consisting of hydrogen, lower-alkyl,
nitro, amino, cyano, and alkylmercapto, preferably, hydrogen, lower-alkyl,
nitro, and amino, more preferably, hydrogen and methyl, and most
preferably, hydrogen.
R.sub.4 and R.sub.5 are independently selected from the group consisting of
hydrogen, lower-alkyl, aryl, and aryl lower-alkyl, or R.sub.4 and R.sub.5
together with the carbon atom to which they are attached form a 5- or
6-member saturated hydrocarbon ring. Preferably, R.sub.4 and R.sub.5 are
selected from the group consisting of hydrogen and methyl, and more
preferably, R.sub.4 and R.sub.5 are methyl.
R.sub.6 is selected from the group consisting of hydrogen, lower-alkyl,
aryl lower-alkyl, formyl, lower-alkyl carbonyl, and aryl carbonyl,
preferably, hydrogen and methyl, and more preferably, methyl.
R.sub.7 is selected from the group consisting of phenyl, thienyl, indolyl,
indazolyl, benzo[b]furanyl, benzo[b]thiophenyl, and the radical R.sub.8
R.sub.9 --N--. In one embodiment, R.sub.7 is selected from the group
consisting of phenyl, thienyl, indolyl, indazolyl, benzo[b]furanyl, and
benzo[b]thiophenyl. Preferably, R.sub.7 is selected from the group
consisting of phenyl, 2-thienyl, 3-thienyl, 2-indolyl, 3-indolyl,
3-indazolyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl, 2-benzo[b]thiophenyl,
and 3-benzo[b]thiophenyl, more preferably, R.sub.7 is selected from the
group consisting of 3-indolyl, 3-indazolyl, and 2-benzo[b]thiophenyl, and
most preferably, R.sub.7 is 2-benzo[b]thiophenyl.
In another embodiment, R.sub.7 is R.sub.8 R.sub.9 --N-- wherein R.sub.8 is
selected from the group consisting of 8-[1,2,3,4-tetrahydroquinolinyl],
3-pyridinyl, 3-quinolinyl, 2-naphthalinyl, 2-thiazolyl, 2-benzothiazolyl,
4-[2,1,3]benzothiadiazolyl, 2-(4,5,6,7-tetrahydrobenzo)thiazolyl,
7-(2,2-dimethyl-2,3-dihydrobenzo)furanyl, and phenyl. Preferably, R.sub.8
is selected from the group consisting of
8-[1,2,3,4,-tetrahydroquinolinyl], 2-pyridinyl, 3-pyridinyl, 3-quinolinyl,
2-naphthalinyl, 2-thiazolyl, 2-benzothiazolyl, 4-[2,1,3]benzothiadiazolyl,
2-(4,5,6,7-tetrahydrobenzo)thiazolyl,
7-(2,2-dimethyl-2,3-dihydrobenzo)furanyl, and phenyl. More preferably,
R.sub.8 is selected from the group consisting of 2-thiazolyl,
2-benzothiazolyl, 4-[2,1,3]benzothiadiazolyl, and phenyl containing one or
more substituents, and more preferably, R.sub.8 is 2-benzothiazolyl and
phenyl.
R.sub.9 is selected from the group consisting of hydrogen and lower-alkyl,
preferably, hydrogen and methyl, and more preferably, hydrogen.
R.sub.8 R.sub.9 --N-- is a radical selected from the group consisting of
1-indolinyl, 1-(3,3-dimethylindolinyl), and
1-(1,2,3,4-tetrahydroquinolinyl), preferably, 1-(3,3-dimethylindolinyl)
and 1-indolinyl, and more preferably, 1-indolinyl.
The groups represented by R.sub.7 other than R.sub.8 R.sub.9 N-- may be
unsubstituted or substituted with one or more substituents selected from
the group consisting of lower-alkyl, lower-alkoxy, di-lower-alkylamino,
and aryloxy, and the groups represented by R.sub.8 and the radical R.sub.8
R.sub.9 N-- may have one or more substituents selected from the group
consisting of hydroxy, halogen, lower-alkyl, lower-alkoxy, amino, mono- or
di-lower-alkylamino, lower-alkyl carbonyl, lower-alkoxy carbonyl, and
aryloxy, wherein each aryloxy group may be unsubstituted or substituted
with one or more substituents independently selected from the group
consisting of lower-alkyl, lower-alkoxy, halogen, and trifluoromethyl.
Preferably, the substituent groups on R.sub.7 are lower-alkyl and the
substituent groups on R.sub.8 and the radical R.sub.8 R.sub.9 N-- are
selected from the group consisting of hydroxy, lower-alkyl carbonyl,
lower-alkoxy carbonyl, and substituted or unsubstituted aryloxy.
In another embodiment, the invention pertains to novel compounds for
treating nausea and vomiting in a mammal mediated through 5-HT.sub.3
receptors and/or other mechanisms. These
4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid derivatives
are represented by the formula:
##STR4##
including optically active isomeric forms, and the pharmaceutically
acceptable acid addition salts thereof, wherein R.sub.1 through R.sub.9
are as defined above with the proviso that, when R.sub.8 is phenyl, the
phenyl group contains at least one substituent independently selected from
the group consisting of hydroxy, amino, lower-alkyl carbonyl, lower-alkoxy
carbonyl, and aryloxy;
wherein the symbol * represents an asymmetric carbon atom at position 6
which may be in the R or S configuration.
The term "lower-alkyl", as used herein, means branched- or
unbranched-hydrocarbon radicals containing from 1 to 6 carbon atoms,
preferably from 1 to 3 carbon atoms. The term "halogen", as used herein,
includes all four halogens with chlorine being preferred. The term "aryl"
means aromatic hydrocarbon radicals such as phenyl, naphthyl, and the
like.
In a preferred embodiment, the compounds of the present invention are
selected from the group consisting of
(R)-6-(2-benzothiazolylaminocarbonyl)-5-methyl-4,5,6,7-tetrahydroimidazo[4
,5-c]pyridine,
(S)-6-(2-hydroxyphenylaminocarbonyl)-5-methyl-4,5,6,7-tetrahydroimidazo[4,
5-c]pyridine,
(S)-6-(2-acetylphenylaminocarbonyl)-5-methyl-4,5,6,7-tetrahydroimidazo[4,5
-c]pyridine,
(S)-6-(2-methoxyphenylaminocarbonyl)-4,4-dimethyl-4,5,6,7-tetrahydroimidaz
o[4,5-c]pyridine,
(S)-6-(2-phenoxyphenylaminocarbonyl)-4,5,6,7-tetrahydroimidazo[4,5-c]pyrid
ine,
(S)-6-(2-phenoxy-phenylaminocarbonyl)-4,4-dimethyl-4,5,6,7-tetrahydroimida
zo[4,5-c]pyridine, and their pharmaceutically acceptable addition salts. In
a more preferred embodiment, the compounds of the present invention are
selected from the group consisting of
(R)-6-(2-benzothiazolyl)aminocarbonyl-5-methyl-4,5,6,7-tetrahydroimidazo[4
,5-c]pyridine,
(S)-6-(2-acetylphenyl)aminocarbonyl-5-methyl-4,5,6,7-tetrahydroimidazo[4,5
-c]pyridine,
(S)-6-(2-phenoxy-phenyl)aminocarbonyl-5-methyl-4,5,6,7-tetrahydroimidazo[4
,5-c]pyridine, and their pharmaceutically acceptable addition salts.
The compounds of the present invention can be prepared by various methods.
In one method set out in Scheme 1, a histidine derivative of type (2) is
reacted with a carbonyl compound having the formula R.sub.4 R.sub.5 CO to
form an intermediate (3) according to the cyclization procedure of Guzman
et al., J. Med. Chem., 27, 564 (1984). R.sub.1 and R.sub.2 in histidine
derivative (2) are as defined above. Starting material histidine
derivatives of type (2), such as L-histidine, D-histidine, D,L-histidine,
1-methyl-L-histidine, 3-methyl-L-histidine, and
alpha-methyl-D,L-histidine, are available commercially from Sigma Chemical
Company, St. Louis, Mo. R.sub.3 in histidine derivative (2) may be
hydrogen. R.sub.4 and R.sub.5 in the carbonyl compound may be the same or
different and may be hydrogen, lower-alkyl, aryl, or aryl lower-alkyl, or
R.sub.4 and R.sub.5 together with the carbon atom to which they are
attached form a 5- or 6-member saturated hydrocarbon ring. The starting
material histidine derivative (2) may be the D-enantiomer or the
L-enantiomer, or may be a mixture of both enantiomers. A D-histidine
derivative (2) yields an intermediate (3) with the R configuration and an
L-histidine derivative yields an intermediate with the S configuration.
Reaction of D-histidine (2) with formaldehyde (HCHO), for example, yields
the intermediate,
(R)-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid (3).
##STR5##
Intermediate (3) may then be optionally reductively alkylated at the
nitrogen atom at position 5 with an aldehyde compound of type R'CHO in the
presence of hydrogen and a catalyst, wherein R' is hydrogen, lower-alkyl,
aryl, or aryl lower-alkyl, and R'CH.sub.2 -- equals R.sub.6 as defined
above, to prepare 5-lower-alkyl or aryl lower-alkyl intermediate (4).
Alternatively, intermediate (3) may be optionally acylated at the nitrogen
atom at position 5 with a compound of type R'COX or (R'CO).sub.2 O,
wherein R' is as defined above and X is a halogen, to prepare 5-acyl
(formyl, lower-alkyl carbonyl, and arylcarbonyl) intermediate (4)
essentially according to the method of Klutchko et al., J. Heterocyclic
Chem., 28, 97 (1991). Reaction of
4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid (3) with
formaldehyde followed by catalytic hydrogenation, for example, yields the
5-methyl intermediate,
5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid (4).
Reaction of 4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6 -carboxylic acid
(3) with acetyl chloride yields the 5-acyl spinacine intermediate,
5-acetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid (4).
5-Lower-alkyl or acyl intermediate (4) or intermediate (3) can then be
converted into a 6-carboxamide-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine
derivative of the present invention having formula (1) by reaction with an
amine selected from the group consisting of R.sub.8 R.sub.9 --NH,
indoline, 3,3-dimethylindoline, and 1,2,3,4-tetrahydroquinoline, and in
the presence of a coupling agent such as a carbodiimide, wherein R.sub.8
and R.sub.9 are as defined above. Reaction of
5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid (4)
with 2-hydroxyaniline, for example, yields
6-(2-hydroxyphenylaminocarbonyl)-5-methyl-4,5,6,7-tetrahydroimidazo-[4,5-c
]pyridine (1).
Intermediate (3) or 5-lower-alkyl or acyl intermediate (4) may also be
converted into a 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylic
acid ester of type (5a) by acid-catalyzed reaction of (3) or (4) with an
alcohol represented by the formula R.sub.10 OH, wherein R.sub.10 is
lower-alkyl. Alternatively, intermediate (4) may also be converted to an
amide of type (5b) by coupling (3) or (4) with an amine in the presence of
a coupling agent such as a carbodiimide. Reaction of
5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylic acid with
(methoxy)methylamine in the presence of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) yields the amide (5b).
Intermediate (5a or 5b) may in turn be converted into a ketone of type (1)
by treatment with a reagent of type R.sub.7 M wherein M is lithium or
MgBr, such as phenyllithium. Reaction of
5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid
methyl ester (5a) or N-methoxy N-methyl amide (5b) with phenyllithium, for
example, yields
6-benzoyl-5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine (1).
Several convenient routes exist for introducing functionalized R.sub.3
groups (lower-alkyl, nitro, amino, cyano, and alkylmercapto) in the
compounds of formula (1) employing known reaction steps. In one method set
out in Scheme 2, the desired compounds having formula (1) can be prepared
by reacting intermediate (4') with a nitrating agent, such as HNO.sub.3
--H.sub.2 SO.sub.4, to form the 2-nitro intermediate (4"). The 2-nitro
derivative (4") may then be treated with an amine of type R.sub.8 R.sub.9
NH to form 2-nitro amide (1'). 2-Nitro amide (1') may then be reduced to
form 2-amino amide (1").
##STR6##
In another method set out in Scheme 3, the desired compounds having formula
(1) can be prepared by alkylating intermediate (4') with an alkylating
agent, such as methyl iodide (CH.sub.3 I), in the presence of a strong
base, such as lithium diisopropyl amide (LDA), to form the 2-alkyl
intermediate (4'").
##STR7##
In yet another method set out in Scheme 4, the desired compounds having
formula (1) can be prepared by reacting intermediate (4') with a
halogenating agent, such as bromine, Br.sub.2, to form the 2-bromo
intermediate (4.sup.iv). The 2-bromo derivative (4.sup.iv) may then be
treated with an anion, such as sodium cyanide or a sodium alkyl mercaptan,
to form the 2-substituted intermediate (4.sup.v).
##STR8##
In a preferred embodiment, the compounds of formula (I) are prepared by a
method which comprises the steps of:
(a) reacting a histidine compound having the formula:
##STR9##
with a carbonyl compound having the formula R.sub.4 R.sub.5 CO to form a
compound (3); wherein R.sub.1 through R.sub.5 are as defined above; and
(b) reacting compound (3) with an amine having the formula R.sub.8 R.sub.9
NH, wherein R.sub.8 and R.sub.9 are as defined above.
In another embodiment, the method further comprises the step of, prior to
step (b), reductively reacting the compound (3) from step (a) with a
compound having the formula R'CHO, wherein R' is as defined above, to form
a 5-alkyl or 5-arylalkyl intermediate (5).
In yet another embodiment, the method further comprises the step of, prior
to step (b), reacting the compound (3) from step (a) with a compound
having the formula R'COX or (R'CO).sub.2 O to prepare a 5-acyl
intermediate (4), wherein R' is as defined above and X is a halogen.
The compounds of the present invention while effective in the form of the
free base may be formulated and administered in the form of
pharmaceutically acceptable acid addition salts for purposes of stability,
convenience of crystallization, increased solubility and the like. These
acid addition salts are formed by conventional methods and include
inorganic acid salts such as the hydrochloride, hydrobromide, sulfate,
phosphate, and the like; and organic acid salts such as acetate,
propionate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,
toluenesulfonate, tartrate, citrate, maleate, fumarate, oxalate, and the
like. The preferred acid addition salts are the hydrochloride,
methanesulfonate, p-toluenesulfonate, and the citrate.
The compounds of the present invention can be combined with a
pharmaceutically acceptable carrier to provide a pharmaceutical
composition. Suitable carriers for the subject compounds as the free base
include propylene glycol-alcohol-water, isotonic water, sterile water for
injection (USP), emulphor.TM.-alcohol-water, cremophor-EL.TM. or other
suitable carriers known to those skilled in the art.
Suitable carriers for the acid addition salts of the subject compounds
include isotonic water, sterile water for injection (USP), alone or in
combination with other solubilizing agents such as ethanol, propylene
glycol, or other conventional solubilizing agents known to those skilled
in the art. A preferred carrier is an isotonic aqueous solution of the
inventive compound.
The compounds of the present invention can be administered to mammals,
e.g., animals or humans, in amounts effective to provide the desired
serotonin antagonist activity. Since the activity of the compounds and the
degree of the desired therapeutic effect vary, the dosage level of the
compound employed will also vary. The actual dosage administered will also
be determined by such generally recognized factors as the body weight of
the patient and the individual hypersensitiveness of the particular
patient. Thus, the unit dosage for a particular patient (man) can vary
from as low as about 0.001 mg per kg of body weight, which the
practitioner may titrate to the desired effect. A preferred minimum dose
for titration is 0.01 mg/kg body weight.
The compounds of the present invention can be administered by recognized
parenteral routes, in the form of sterile solutions or suspensions, in the
carriers previously described. These preparations should contain at least
about 0.1%, by weight, of the inventive compound but this amount may be
varied to between about 0.1% and about 50%, by weight, of the inventive
compound. The compounds of the present invention are preferably
administered intravenously and the dosage used will generally be in the
range from about 0.001 mg to about 500 mg, and preferably from about 0.01
mg to about 50 mg, per 70 kg body weight. This dosage may be administered
from 1 to 4 times daily.
The sterile solutions or suspensions may also include the following
adjuvants: a sterile diluent, such as water for injection, saline
solution, fixed oils, polyethylene glycol, glycerine, propylene glycol, or
other synthetic solvent; antibacterial agents, such as benzyl alcohol or
methyl paraben; antioxidants, such as ascorbic acid or sodium
metabisulfite; chelating agents, such as ethylenediaminetetraacetic acid
(EDTA); buffers, such as acetates, citrates or phosphates; and agents for
the adjustment of tonicity, such as sodium chloride or dextrose. The
parenteral preparations may be enclosed in ampules, disposable syringes,
or multiple dosage vials made of glass or plastic.
Throughout this application, various publications have been referenced. The
disclosures in these publications are incorporated herein by reference in
order to more fully describe the state of the art.
The present invention is further illustrated by the following examples
which are presented for purposes of demonstrating, but not limiting, the
preparation of the compounds and compositions of this invention. In
addition to the parameters set out below, the identity of each compound
prepared was confirmed by Nuclear Magnetic Resonance, Infrared
Spectroscopy, or both.
EXAMPLE 1
This Example illustrates the preparation of the intermediate
(R)-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid
hydrochloride ((R)-3a), compound 3 in Scheme 1 wherein R.sub.1 through
R.sub.5 are hydrogen.
Formaldehyde (37% aqueous solution, 15.617 g, 193 mmol) was slowly added to
a solution of D-histidine hydrochloride monohydrate (25,025 g, 119 mmol)
in water (250 ml) and the mixture was heated to reflux for 1 hour. The
solvent was evaporated under vacuum and the residue washed with methanol
to yield (R)-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid
hydrochloride ((R)-3a) as a white solid (23.199 g, 95.4% yield, dried at
60.degree. C. at 1 mm Hg for 18 hours). m.p.: 283.degree. C. (dec.).
Anal. calcd. for C.sub.7 H.sub.9 N.sub.3 O.sub.2.HCl: C, 41.29; H, 4.95; N,
20.64. Found: C, 41.34; H, 4.85; N, 20.37.
When the above reaction was carried out using L-histidine hydrochloride
monohydrate, (S)-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic
acid hydrochloride ((S)-3a) was obtained. m.p.: 290.degree. C. (dec.)
(276.degree. C.; Akabori et al., Bull. Chem. Soc., Jap. 31, 784 (1958)).
Anal. calcd. for C.sub.7 H.sub.9 N.sub.3 O.sub.2.HCl: C, 41.29; H, 4.95; N,
20.64. Found: C, 41.03; H, 5.07; N, 20.51.
EXAMPLE 2
This Example illustrates the preparation of the intermediate
(S)-4,4-dimethyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic
acid hydrochloride ((S)-3b), compound 3 in Scheme 1 wherein R.sub.1
through R.sub.3 are hydrogen and R.sub.4 and R.sub.5 are methyl.
L-Histidine hydrochloride monohydrate (20 g, 94.5 mmol) was dissolved in
water (500 ml) and acetone (100 ml) and the resulting solution was made
alkaline (pH 12) by treatment with sodium hydroxide solution (50% w/w) and
heated to reflux overnight. The reaction mixture was then passed through a
column of AG-1.times.8 ion exchange resin (300 meq., hydroxide form).
After removal of impurities from the column by elution with water, the
product was eluted with 1.8% hydrochloric acid. The solvent was evaporated
under vacuum and the residue recrystallized from methanol to yield
(S)-4,4-dimethyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic
acid dihydrochloride ((S)-3b) as a solid (18.4 g, 100% yield). m.p.:
240.degree. C. (dec.).
Anal. calcd. for C.sub.9 H.sub.13 N.sub.3 O.sub.2.HCl.1/4 H.sub.2 O: C,
39.65; H, 5.73; N, 15.41. Found: C, 39.61; H, 6.07; N, 15.06.
EXAMPLE 3
This Example illustrates the preparation of the intermediate
(R)-5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid
hydrochloride ((R)-4a), compound 4 in Scheme 1 wherein R.sub.1 through
R.sub.5 are hydrogen and R.sub.6 is methyl.
Palladium hydroxide (Pd content 20%, 0.7 g) was added to a solution of
compound (R)-3a from Example 1 (16.5 g, 81.1 mmol) and formaldehyde (37%
aqueous solution, 8.9 g, 110 mmol) in water (100 ml). The mixture was then
hydrogenated on a Parr apparatus (51 psi) at room temperature overnight.
After removal of the catalyst by filtration, the filtrate was concentrated
under vacuum to yield a foaming solid (19.8 g). The foaming solid (15.1 g)
was dissolved in water (30 ml) and passed through a column of AG-50W-X8
ion exchange resin (344 meq, hydrogen form). After removal of impurities
from the column by elution with water, the product was eluted with 1.5%
ammonium hydroxide solution. After removal of the solvent under vacuum,
the residue was triturated with 1,4-dioxane to yield
(R)-5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid
((R)-4a) as a solid (11.1 g, 91% yield). m.p.: 263.degree.-265.degree. C.
Anal. calcd. for C.sub.8 H.sub.11 N.sub.3 O.sub.2 : C, 53.03; H, 6.12; N,
23.19. Found: C, 52.93; H, 6.09; N, 23.25.
When the above reaction was carried out using (S)-spinacine from Example 1,
(S)-5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid
hydrochloride ((S)-4a) was obtained, m.p.: 262.degree.-263.degree. C.
Anal. calcd. for C.sub.8 H.sub.11 N.sub.3 O.sub.2 : C, 53.03; H, 6.12; N,
23.19. Found: C, 53.09; H, 6.00; N, 23.00.
EXAMPLE 4
This Example illustrates the preparation of the intermediate
(S)-4,4-dimethyl-5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carb
oxylic acid dihydrochloride ((S)-4b), compound 4 in Scheme 1 wherein
R.sub.1 through R.sub.3 are hydrogen and R.sub.4 through R.sub.6 are
methyl.
Palladium hydroxide (Pd content 20%, 3.5 g) was added to a solution of
(S)-3b from Example 2 (15 g, 76.8 mmol) and formaldehyde (37% aqueous
solution, 10 g, 123 mmol) in water (80 ml). The mixture was then
hydrogenated on a Parr apparatus (51 psi) at room temperature overnight.
After removal of the catalyst by filtration, the filtrate was concentrated
under vacuum to yield a foaming solid which was slurried in water (30 ml)
and passed through a column of AG-50W-X8 ion exchange resin (300 meq,
hydrogen form). After removal of impurities from the column by elution
with water, the product was eluted with 1.5% ammonium hydroxide solution.
After removal of the solvent under vacuum, the residue was acidified with
hydrochloric acid and recrystallized from methanol to yield
(S)-4,4-dimethyl-5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carb
oxylic acid dihydrochloride ((S)-4b) as a solid (15.2 g, 94.5% yield).
m.p.: 210.degree. C. (dec.).
Anal. calcd. for C.sub.10 H.sub.15 N.sub.3 O.sub.2.2HCl.CH.sub.3 OH: C,
42.05; H, 6.74; N, 13.37. Found: C, 41.80; H, 6.81; N, 13.37.
EXAMPLE 5
This Example illustrates the preparation of the intermediate
(S)-5-ethyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid
((S)-4c), compound 4 in Scheme 1 wherein R.sub.1 through R.sub.5 are
hydrogen and R.sub.6 is ethyl.
Palladium hydroxide (Pd content 20%, 0.8 g) was added to a solution of
(S)-3a from Example 1 (15.5 g, 76 mmol) and acetaldehyde (9.8 g, 220 mmol)
in 80 ml of water. The mixture was then hydrogenated on a Parr apparatus
(54 psi) at room temperature overnight. After removal of the catalyst by
filtration, the filtrate was concentrated under vacuum to yield a foaming
solid (19.1 g). The foaming solid (15.0 g) was dissolved in water (25 ml)
and passed through a column of AG-50W-X8 ion exchange resin (300 meq,
hydrogen form). After removal of impurities from the column by elution
with water, the product was eluted with 1.5% ammonium hydroxide solution.
After removal of the solvent under vacuum, the residue yielded
(S)-5-ethyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid
((S)-4c) as a solid (10.2 g, 73.9% yield). m.p.: 185.degree. C. (dec.)
Anal. calcd. for C.sub.9 H.sub.13 N.sub.3 O.sub.2 : MW 195.22; MS
m/z=195[M+].
EXAMPLE 6
This Example illustrates a general method for the preparation of
4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxamide derivatives
according to the present invention.
Compound 3 (Scheme 1) (5 mmol) or a substituted derivative (4) was
dissolved in water (5 ml) and hydrochloric acid (5 ml, 1N) and cooled to
0.degree. C. A water-soluble carbodiimide, such as
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (5.6 mmol), was added to the
solution in portions with stirring. After the mixture was stirred at
0.degree. C. for 15 minutes, the desired amine (6 mmol) in
dimethylformamide (5 ml), or water (5 ml) if necessary for solubility, was
added to the solution. The reaction mixture was then allowed to warm to
room temperature and was stirred for two days. The reaction mixture was
made alkaline (pH 8) with sodium hydroxide solution (50% w/w) and the
solvent was removed under vacuum. The residue was chromatographed on a
silica gel column using 8-15% methanol in methylene chloride. After
removing the solvent under vacuum, the free base amide was converted to
the dihydrochloride in methanol using hydrogen chloride in ethyl ether to
yield the desired amide dihydrochloride (1).
EXAMPLE 7
This Example illustrates the preparation of
(S)-5-methyl-6-(2-phenoxyphenylaminocarbonyl)-4,5,6,7-tetrahydroimidazo[4,
5-c]pyridine dihydrochloride.
To a stirred suspension of
(S)-5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine monohydrochloride
(3.39 g, 15.6 mmol) in 6.8 ml of dimethylformamide,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.99 g, 15.6
mmol) was added portionwise over 25 minutes at ice bath temperature. The
ice bath was removed and a solution of 2-phenoxyaniline (2.89 g, 15.6
mmol) in 10.3 ml of dimethylformamide was added dropwise. After being
stirred for 40 hours, the reaction mixture was diluted with water and
extracted with methylene chloride. The methylene chloride layer was dried
over sodium sulfate (Na.sub.2 SO.sub.4) and the solvent was removed in
vacuo. The residue was chromatographed over silica gel and eluted
successively with methylene chloride, methylene chloride:methanol (98:2)
and methylene chloride:methanol (95:5) to yield 1.02 g (20%) of the free
base. The dihydrochloride salt was recrystallized from 2-propanol, m.p.:
205.degree.-208.degree. C.; [.alpha.].sub.D =-27.9.degree. at 25.degree.
C. in methanol (c=0.85).
Anal. calcd. for C.sub.20 H.sub.20 N.sub.4 O.sub.2.2HCl: C, 57.01; H, 5.26;
N, 13.30. Found: C, 57.05; H, 5.43; N, 13.17.
EXAMPLE 8
This Example illustrates the preparation of
(S)-6-(2,5-dimethoxyphenylaminocarbonyl)-5-methyl-4,5,6,7-tetrahydoimidazo
[4,5-c]pyridine dihydrochloride.
(S)-6-(2,5-Dimethoxyphenylaminocarbonyl)-5-methyl-4,5,6,7-tetrahydoimidazo[
4,5-c]pyridine dihydrochloride was prepared in 50% yield by the procedure
set out above. Physical properties of the dihydrochloride salt: m.p.:
160.degree. C. (dec.); [.alpha.].sub.D =-50.9.degree. C. in methanol
(c=1.0).
Anal. calcd. for C.sub.16 H.sub.20 N.sub.4 O.sub.3.2HCl.H.sub.2 O: C,
47.18; H, 5.94; N, 13.76. Found: C, 47.49; H, 5.88; N, 13.81.
EXAMPLE 9
This Example illustrates the preparation of
(S)-6-(2,5-dihydroxyphenylaminocarbonyl)-5-methyl-4,5,6,7-tetrahydroimidaz
o[4,5-c]pyridine dihydrobromide.
To a stirred slurry of the above 2,5-dimethoxy compound (free base) (1.0 g,
3.2 mmol) in 20 ml of methylene chloride, BBr.sub.3 (22 ml of 1M solution
in methylene chloride, 22.0 mmol) was added at -78.degree. C. The reaction
mixture was gradually brought to room temperature and stirred for 48
hours. The excess BBr.sub.3 was decomposed by dropwise addition of
methanol at -20.degree. C. and the contents were evaporated to dryness.
The dihydrobromide salt was purified by reprecipitation from
methanol-ether. Yield 1.1 g (76%), m.p.: 192.degree. C.
Anal. calcd. for C.sub.14 H.sub.16 N.sub.4 O.sub.3.2HBr: C, 37.36; H, 4.03;
N, 12.45. Found: C, 37.41; H, 4.32; N, 12.19.
EXAMPLE 10
This Example illustrates the preparation of
(S)-5-acetyl-6-(2-methoxyphenylaminocarbonyl)-4,5,6,7-tetrahydroimidazo[4,
5-c]pyridine hydrochloric acid.
Sodium hydride (80% dispersion in mineral oil, 0.55 g, 18 mmol) was added
to a solution of
(S)-6-(2-methoxyphenyl)aminocarbonyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyrid
ine (2.00 g, 7 mmol) in anhydrous N,N-dimethylformamide (70 ml). The
reaction mixture was heated to 80.degree. C. for 30 minutes, then allowed
to cool to room temperature. Acetyl chloride (1.46 g, 18 mmol) was added
to the reaction mixture at 0.degree. C. The reaction mixture was allowed
to warm to room temperature, stirred overnight, and brought to pH 8. Water
and N,N-dimethylformamide was distilled off under vacuum. The residue was
chromatographed on silica gel with a solvent system of ammonium
hydroxide/methanol/methylene chloride (1/8/92 v/v) to yield
(S)-5-acetyl-6-(2-methoxyphenylaminocarbonyl)-4,5,6,7-tetrahydroimidazo[4,
5-c]pyridine (free base) (1.13 g, 49%). The free base was converted to the
hydrochloric acid salt: m.p.: 159.degree. C.
Anal. calcd. for C.sub.16 H.sub.18 N.sub.4 O.sub.3.HCl.H.sub.2 O: C, 52.11;
H, 5.74; N, 15.19. Found: C, 52.04; H, 5.63; N, 15.03.
EXAMPLE 11
This Example illustrates the preparation of an ester,
(S)-5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid
ethyl ester ((S)-5a), compound 5a in Scheme 1 wherein R.sub.1 through
R.sub.5 are hydrogen, R.sub.6 is methyl, and R.sub.10 is ethyl.
Compound 4a from Example 3 (20 g, 91.9 mmol) was dissolved in absolute
ethanol (600 ml) and concentrated sulfuric acid (10 ml) and heated to
reflux under a Dean-Stark trap for 24 hours. The solvent was evaporated
under vacuum and the residue was neutralized (pH 7) with 1N sodium
carbonate solution. The aqueous solution was extracted with methylene
chloride (5.times.160 ml) and the combined organic extracts concentrated.
The crude residue was chromatographed on a silica gel column eluting with
10% methanol in methylene chloride to yield
(S)-5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid
ethyl ester ((S)-5a) as a solid (12.7 g, 66.1% yield). m.p.: 72.degree. C.
Anal. calcd. for C.sub.10 H.sub.15 N.sub.3 O.sub.2.0.6 H.sub.2 O: C, 54.58;
H, 7.42; N, 19.10. Found: C, 54.62; H, 7.29; N, 19.32.
When the above reaction was carried out using compound 4a from Example 3
and methanol instead of ethanol,
(R)-5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid
methyl ester ((R)-5b) was obtained, compound 5 in Scheme 1 wherein R.sub.1
through R.sub.5 are hydrogen and R.sub.6 and R.sub.10 are methyl.
Anal. calcd. for C.sub.9 H.sub.13 N.sub.3 O.sub.2 : C, 55.37; H, 6.71; N,
21.52. Found: C, 55.36; H, 6.98; N, 21.19.
EXAMPLE 12
This Example illustrates the preparation of a representative example of
ketone compound 1 in Scheme 1,
(R)-6-benzoyl-5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine oxalic
acid).
Phenyllithium (2M cyclohexane/diethyl ether solution (70:30), 6 ml, 12
mmol) was added to a solution of
(R)-5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid
methyl ester from Example 11 (5b, 1.27 g, 6.07 mmol) in dry
tetrahydrofuran (50 ml) at -78.degree. C. The reaction mixture was
maintained at -78.degree. C. for 15 minutes, then allowed to warm to room
temperature. Ethyl acetate (2 ml) was added to the reaction mixture and
the solvents were removed under vacuum. The residue was mixed with water
(25 ml) and then extracted with methylene chloride. The combined extracts
were dried over anhydrous sodium sulfate and evaporated under vacuum. The
crude residue (2.38 g) was chromatographed on an alumina column eluting
with 3% methanol in methylene chloride to yield
(R)-6-benzoyl-5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine as a solid
(0.406 g, 35% yield). The free base was recrystallized from methanol/ethyl
acetate/methyl t-butyl ether. A portion (0.377 g, 1.56 mmol) of the
recrystallized free base was converted to its oxalic acid salt (0.436 g,
100% based on oxalic acid used). m.p.: 98.degree. C.
Anal. calcd. for C.sub.14 H.sub.15 N.sub.3 O: C, 58.00; H, 5.17; N, 12.68.
Found: C, 58.29; H, 5.41; N, 12.58.
EXAMPLE 13
This Example illustrates the preparation of
6-(N-methoxy-N-methylaminocarbonyl-4,5,6,7)-tetrahydroimidazo[4,5-c]pyridi
ne (5b).
To a solution of
(S)-5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylic acid
(5.0 g, 27.6 mmol) in water (50 ml) was added O,N-dimethylhydroxylamine
hydrochloride (2.83 g, 28.98 mmol) followed by
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.33 g, 27.88
mmol). The reaction mixture was stirred at room temperature for 2 days.
The pH of the reaction mixture was adjusted to approximately 8 by addition
of 10% sodium carbonate solution and the solvents were removed under
reduced pressure. The residual semisolid was triturated with methanol and
filtered. The methanol filtrate was evaporated under reduced pressure and
the residual material was purified on a silica gel column by elution with
5% methanol in methylene chloride followed by 10% methanol in methylene
chloride both containing 0.5% ammonium hydroxide. The desired amide 5b was
obtained (4.15 g, 67.1% yield) as white crystals. m.p.:
128.degree.-129.degree. C.;
Anal. calcd. for C.sub.10 H.sub.16 N.sub.4 O.sub.2 : C, 53.56; H, 7.19; N,
24.98. Found: C, 53.23; H, 7.15; N, 25.12.
EXAMPLE 14
This Example illustrates the preparation of
6-(2-benzo[b]thiophenylcarbonyl)-5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]
pyridine.
To a flame dried three-neck round bottom flask containing thianaphthene
(3.84 g, 28.62 mmol) in anhydrous ether (50 ml) under nitrogen, cooled by
an ice bath, was added by syringe, a solution of 1.6M n-butyllithium in
hexanes (20 ml, 32 mmol). The mixture was stirred at room temperature for
1 hour and then cooled (ice bath). Compound 5b described above (2.57 g,
11.45 mmol) dissolved in anhydrous tetrahydrofuran (130 ml) was added by
syringe. The reaction mixture was stirred at ice bath temperature for 3
hours. The pH of the reaction mixture was made acidic by addition of 5%
hydrochloric acid in ethanol and the mixture was concentrated under
reduced pressure. The residual material was diluted with water and
extracted with methylene chloride. The pH of the aqueous portion was
adjusted to about 7-8 by addition of sodium bicarbonate. Attempted
partition of the product into ethyl acetate resulted in precipitation of
fine off-white solids. The solids were filtered and dried under vacuum
(2.34 g, 69% yield). m.p.: 180.degree.-183.degree. C.
The material described above (2.0 g) was dissolved in methanol and
filtered. To this solution was added 1M hydrochloric acid solution in
ether (17 ml). The solution was mixed well, evaporated under reduced
pressure, and the solids recrystallized from methanol-ether. The slightly
off-white crystals obtained were dried under vacuum at 60.degree. C.
overnight (1.84 g). m.p.: 233.degree.-235.degree. C.
Anal. calcd. for C.sub.16 H.sub.15 N.sub.3 OS.2HCl: C, 51.90; H, 4.63; N,
11.35. Found: C, 51.60; H, 4.61; N, 11.18.
EXAMPLE 15
This Example illustrates the preparation of
6-(2-benzo[b]furanylcarbonyl)-5-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyr
idine.
To a solution of 2,3-benzofuran (2.0 ml, 18.15 mmol, in 50 ml of anhydrous
ether) was added 1.6M n-butyllithium in hexanes (12.5 ml, 20 mmol). To the
2-benzofuranyl lithium formed by stirring the solution at room temp. for 1
hour was added (ice bath) the compound 5(b) (1.62 g, 7.22 mmol) dissolved
in anhydrous tetrahydrofuran (70 ml). The reaction was continued at
ice-bath temperature for 3 hours then worked-up as described to afford
0.89 g (44%) of product as off-white solids. This material was converted
to the dihydrochloride by addition of 1M hydrochloric acid in ether (8 ml)
as described. The dihydrochloride obtained was recrystallized from
methanol-ether and dried under vacuum at 60.degree. C. overnight to afford
the ketone dihydrochloride as off-white crystals (0.82 g). m.p.:
193.degree.-195.degree. C.
Anal. calcd. for C.sub.16 H.sub.15 N.sub.3 O.sub.2.2HCl.1/2H.sub.2 O: C,
52.90; H, 4.99; N, 11.57. Found: C, 52.52; H, 5.01; N, 11.28.
EXAMPLES 16-64
Further examples of
4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxamides and ketones
within the scope of the present invention which were prepared by
procedures analogous to those described above include those set out below
in Table 1.
TABLE 1
__________________________________________________________________________
Chemical Data of 4,5,6,7-Tetrahydroimidazo[4,5-c.pi.pyridinyl-6-carboxylic
acid Derivatives
##STR10##
*C.sub.6 m.p.
Con- % .degree.C.
Compd
fig.
R.sub.1
R.sub.2
R.sub.3
R.sub.4
R.sub.5
R.sub.6
R.sub.7 Yield
(dec.)
Formula
__________________________________________________________________________
1 R H H H H H CH.sub.3
2-HOC.sub.6 H.sub.4 NH
37 188 C.sub.14 H.sub.16
N.sub.4 O.sub.2.2HCl.0.5H
.sub.2 O
2 R H H H H H CH.sub.3
5-Cl-2-CH.sub.3 OC.sub.6 H.sub.3 NH
49 188 C.sub.15 H.sub.17
N.sub.4
O.sub.2 Cl.2HCl.0.5H.sub.
2 O
3 R H H H H H CH.sub.3
2-CH.sub.3 OC.sub.6 H.sub.4 NH
65 180 C.sub.15 H.sub.18
N.sub.4 O.sub.2.2HCl
4 R H H H H H CH.sub.3
2-COOCH.sub.3 C.sub.6 H.sub.4 NH
17 169 C.sub.16 H.sub.18
N.sub.4 O.sub.3.2HCl
5 R H H H H H CH.sub.3
2-COCH.sub.3 C.sub.6 H.sub.4 NH
16 180 C.sub.16 H.sub.18
N.sub.4 O.sub.2.2HCl.0.25
H.sub.2 O
6 S H H H H H CH.sub.3
2-CH.sub.3 OC.sub.6 H.sub.4 NH
96 178 C.sub.15 H.sub.18
N.sub.4 O.sub.2.2HCl.0.5H
.sub.2 O
7 S H H H H H CH.sub.3
5-Cl-2-CH.sub.3 OC.sub.6 H.sub.3 NH
26 185 C.sub.15 H.sub.17
N.sub.4 O.sub.2.2HCl
8 R H H H H H H 2-CH.sub.3 OC.sub.6 H.sub.4 NH
49 253 C.sub.14 H.sub.16
N.sub.4 O.sub.2.2HCl.0.25
H.sub.2 O
9 R H H H H H CH.sub.3
C.sub.6 H.sub.5 NH
59 208 C.sub.14 H.sub.16
N.sub.4 0.2HCl
10 R H H H H H CH.sub.3
2-C.sub.2 H.sub.5 OC.sub.6 H.sub.4 NH
23 187 C.sub.16 H.sub.20
N.sub.4 O.sub.2.2HCl
11 R H H H H H CH.sub.3
2-C.sub.6 H.sub.5 OC.sub.6 H.sub.4 NH
17 192 C.sub.20 H.sub.20
N.sub.4 O.sub.2.2HCl.0.25
H.sub.2 O
12 R H H H H H CH.sub.3
2-thiadiazolyl-NH
28 200 C.sub.11 H.sub.13
N.sub.5 OS.3HCl.0.5H.sub.
2 O
13 R H H H H H CH.sub.3
2-benzothiazolyl-NH
17 215 C.sub.15 H.sub.15
N.sub.5 OS.2HCl
14 S H H H H H H 2-CH.sub.3 OC.sub.6 H.sub.4 NH
71 243 C.sub.14 H.sub.16
N.sub.4 O.sub.2 2HCl
15 S H H H H H CH.sub.3
2-HOC.sub.6 H.sub.4 NH
20 202 C.sub.14 H.sub.16
N.sub.4 O.sub.2.2HCl
16 S H H H H H CH.sub.3
2-COOCH.sub.3 C.sub.6 H.sub.4 NH
15 174 C.sub.16 H.sub.18
N.sub.4 O.sub.3.2HCl
17 S H H H H H CH.sub.3
2-C.sub.2 H.sub.5 OC.sub.6 H.sub.4 NH
9 157 C.sub.16 H.sub.20
N.sub.4 O.sub.2.2HCl.0.75
H.sub.2 O
18 S H H H H H C.sub.2 H.sub.5
2-HOC.sub.6 H.sub.4 NH
25 130 C.sub.15 H.sub.18
N.sub.4 O.sub.2.2C.sub.2
H.sub.2 O.sub.4
19 R H H H H H CH.sub.3
C.sub.6 H.sub.5 35 98 C.sub.14 H.sub.15
N.sub.3 O.C.sub.2
H.sub.2 O.sub.4
20 S H H H CH.sub.3
CH.sub.3
CH.sub.3
2-CH.sub.3 OC.sub.6 H.sub.4 NH
7 210 C.sub.16 H.sub.20
N.sub.4 O.sub.2.2HCl.1.0H
.sub.2 O
21 R H H H H H CH.sub.3
4-[2,1,3-benzothiadiazol]yl-NH
16 200 C.sub.14 H.sub.14
N.sub.6 OS.2HCl.0.75H.sub
.2 O
22 S H H H H H CH.sub.3
2-benzothiazolyl-NH
12 213 C.sub.15 H.sub.15
N.sub.5 OS.2HCl.1.25H.sub
.2 O
23 S H H H H H CH.sub.3
4-[2,1,3-benzothiadiazol]yl-NH
8 168 C.sub. 14 H.sub.14
N.sub.6 OS.2HCl
24 S H H H CH.sub.3
CH.sub.3
CH.sub.3
2-HOC.sub.6 H.sub.4 NH
19 205 C.sub.16 H.sub.20
N.sub.4 O.sub.2.2HCl
25 S H H H CH.sub.3
CH.sub.3
CH.sub.3
2-CH.sub.3 OC.sub.6 H.sub.4 NH
24 190 C.sub.17 H.sub.22
N.sub.4 O.sub.2.2HCl.0.25
H.sub.2 O
26 S H H H H H CH.sub.3
2-C.sub.6 H.sub.5 C(O)NHC.sub.6 H.sub.4 NH
28 205 C.sub.21 H.sub.21
N.sub.5 O.sub.2.2HCl
27 S H H H H H CH.sub.3
2-C.sub.6 H.sub.5 OC.sub.6 H.sub.4 NH
49 205-
C.sub.20 H.sub.20
N.sub.4 O.sub.2.2HCl
208
28 S H H H H H CH.sub.3
2-thienyl 56 199-
C.sub.21 H.sub.13
N.sub.3 OS.2HCl
201
29 S H H H H H CH.sub.3
2-FC.sub.6 H.sub.4 NH
47 95-
C.sub.14 H.sub.15
N.sub.4 OF.2HCl
97
30 S H H H H H CH.sub.3
2,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 NH
53 160 C.sub.16 H.sub.20
N.sub.4 O.sub.2.2HCl.1.0H
.sub.2 O
31 S H H H H H CH.sub.3
2,3-(F).sub.2 C.sub.6 H.sub.3 NH
39 150 C.sub.14 H.sub.14
N.sub.4 OF.sub.2.2HCl.1.0
H.sub.2 O
32 S H H H H H CH.sub.3
2-benzo[b]thiophenyl
69 233-
C.sub.16 H.sub.15
N.sub.3 OS.2HCl
235
33 S H H H H H CH.sub.3
2-benzo[b]furanyl
78 193-
C.sub.16 H.sub.15
N.sub.3 O.sub.2.2HCl.0.5H
.sub.2 O
195
34 S H H H H H CH.sub.3
2,6-(F).sub.2 C.sub.6 H.sub.3 NH
23 125 C.sub.14 H.sub.14
N.sub.4 OF.sub.2.2HCl.1.2
5H.sub.2 O
35 S H H H H H CH.sub.3
2,3,4-(F).sub.3 C.sub.6 H.sub.2 NH
30 139 C.sub.14 H.sub.13
N.sub.4 OF.sub.
3.2HCl.1.0H.sub.2 O
36 S H H H H H CH.sub.3
8-(1,2,3,4-tetrahydro-
29 133 C.sub.17 H.sub.21
N.sub.5 0.3HCl.0.5H.sub.2
O
quinolin)yl-NH
37 S H H H H H CH.sub.3
2-ClC.sub.6 H.sub.4 NH
18 143 C.sub.14 H.sub.15
N.sub.4 OCl.2HCl
38 S H H H H H CH.sub.3
C.sub.6 H.sub.5 38 95-
C.sub.14 H.sub.15
N.sub.3 O.C.sub.2
H.sub.2 O.sub.4
98
39 S H H H H H CH.sub.3
2-CH.sub.3 C(O)C.sub.6 H.sub.4 NH
26 191 C.sub.16 H.sub.18
N.sub.4 O.sub.2.2HCl.0.5H
.sub.2 O
40 S H H H H H CH.sub.3
2,5-(OH).sub.2 C.sub.6 H.sub.3 NH
78 192 C.sub.14 H.sub.16
N.sub.4 O.sub.2.2HBr
41 S H H H H H CH.sub.3
2-(5-(CH.sub.3 O)-benzo[b]furan)yl-
63 214-
C.sub.17 H.sub.17
N.sub.3 O.sub.3.2HCl.1.0H
.sub.2 O
218
42 S H H H H H CH.sub.3
2-NH.sub.2 C.sub.6 H.sub.4 NH
13 200 C.sub.14 H.sub.17
N.sub.5 O.3HCl.0.5H.sub.2
O
43 S H H H H H CH.sub.3
2-CH.sub.3 OC.sub.6 H.sub.4
54 221-
C.sub.15 H.sub.17
N.sub.3 O.sub.2.2HCl
223
44 S H H H H H CH.sub.3
2-(3-CF.sub.3 C.sub.6 H.sub.4 O)C.sub.6 H.sub.4
NH 54 235-
C.sub.21 H.sub.19
N.sub.4 O.sub.2 F.sub.3.2
HCl
237
45 S H H H H H CH.sub.3
2-(3-FC.sub.6 H.sub.4 O)C.sub.6 H.sub.4 NH
29 120 C.sub.20 H.sub.19
N.sub.4 O.sub.2.2HCl
46 S H H H H H CH.sub.3
2,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.4 NH
84 229-
C.sub.16 H.sub.20
N.sub.4 O.sub.3.2HCl.0.25
H.sub.2 O
231
47 S H H H H H CH.sub. 3 CO
2-CH.sub.3 OC.sub.6 H.sub.4 NH
49 159 C.sub.16 H.sub.18
N.sub.4 O.sub.3.2HCl.1.0H
.sub.2 O
48 S H H H CH.sub.3
CH.sub.3
H 2-CH.sub.3 COC.sub.6 H.sub.4 NH
22 210 C.sub.17 H.sub.20
N.sub.4 O.sub.2.2HCl.0.75
H.sub.2 O
49 S H H H CH.sub.3
CH.sub.3
H 2-C.sub.6 H.sub.5 OC.sub.6 H.sub.4 NH
17 204 C.sub.21 H.sub.22
N.sub.4 O.sub.2.2HCl.0.5H
.sub.2 O
__________________________________________________________________________
EXAMPLE 65
A pharmaceutical composition for antagonism of 5-HT.sub.3 receptors can be
prepared from the following ingredients:
______________________________________
COMPONENTS AMOUNTS
______________________________________
(S)-6-(2-hydroxyphenylamino-
1-30 mg
carbonyl)-5-methyl-4,5,6,7-tetrahydro-
imidazo[4,5-c]pyridine
isotonic water 1 ml
______________________________________
Of course, other compounds of this invention such as those set out in
Examples 16-64 may be utilized as the active component in the above
formulation.
EXAMPLE 66
A number of compounds in accordance with the present invention were tested
for their 5-HT.sub.3 and D.sub.2 binding affinities in accord with the
following procedures.
Binding Methodologies for 5-HT.sub.3 and D.sub.2 Assays
Male Sprague-Dawley rats (175-220 g) were sacrificed by decapitation and
their brains removed rapidly. The entorhinal cortex was used for the
5-HT.sub.3 (5-hydroxytryptamine) binding assay and the remainder of the
brain, minus the brain stem and cerebellum, was used for the D.sub.2
(dopamine) binding assay. The entorhinal cortex was harvested and prepared
on the day of the assay.
The entorhinal cortex was homogenized in 20 volumes of cold 50 mM HEPES
buffer, pH 7.4, while the remaining brain tissue was homogenized in 20
volumes of cold 50 mM Tris, pH 7.4. The homogenates were centrifuged at
4800.times.g for 15 minutes at 5.degree. C. and the supernatants decanted.
Pellets were resuspended in the original volume of HEPES or Tris.
Homogenates were centrifuged and the supernatants decanted. Pellets were
resuspended in the same volume of HEPES or Tris and incubated at
37.degree. C. for 45 minutes to remove endogenous neurotransmitters.
Homogenates were centrifuged and the supernatants were decanted. Pellets
for D.sub.2 assays were stored at -50.degree. C. until the day of the
assay. The pellets for the 5-HT.sub.3 assay (entorhinal cortex) were
resuspended in the appropriate amount of HEPES buffer and used promptly.
Modifications of published assays for [.sup.3 H]GR65630 (Kilpatrick et
al., Nature: 330, 746-748 (1987)) and [.sup.3 H]raclopride (Dewar et al.,
J. Pharmacol. Exp. Ther.: 250, 696-706 (1989) and Lidow et al., Proc.
Natl. Acad. Sci. USA: 86, 6412-6416 (1989)) were used for the 5-HT.sub.3
and D.sub.2 binding assays, respectively.
Briefly, 0.25 ml of homogenate was incubated with either 0.2 nM of [.sup.3
H]GR65630 or 1.0 nM of [.sup.3 H]raclopride in a final volume of 0.5 ml.
D.sub.2 binding also requires sodium chloride and potassium chloride (120
mM and 5 mM, final concentration, respectively). In the 5-HT.sub.3 assay,
non-specific binding was defined in the presence of 100 uM quipazine. In
the D.sub.2 assay, non-specific binding was defined in the presence of 100
uM of (+/-) sulpiride. Both assays were incubated at room temperature;
[.sup.3 H]GR65630 for 40 minutes and [.sup.3 H]raclopride for 60 minutes.
Test compounds (0.1 ml) were added to incubates where appropriate. Bound
ligand was separated from free ligand by filtration and quantified using
liquid scintillation spectrophotometry. IC.sub.50 values were calculate
for all test compounds.
Cisplatin Ferret Assay--Antiemetic Screening
Male ferrets (castrated, descented, 1-2 kg) were purchased from Triple F
Farms, Syre, Pa. Ferrets were housed four in a cage with a 12 hour light
cycle and were fed ad libitum with Ralston Purina Cat Chow. Each ferret
was used unfasted for the assay after a minimum of a 24 hour acclimation
time in animal facility.
Ferret Preparation. Each ferret was anesthetized with 5% isoflurane-O.sub.2
in a 20 gallon aquarium for 2 to 5 minutes. After removal of the
anesthetic gas, the animals were removed and weighed. Injections were made
into the dorsal front paw vein using a tourniquet and a 1 ml tuberculin
syringe with a 25 g needle while the animal was maintained under
anesthesia using a small nose cone delivering 5% isoflurane-O.sub.2.
Cisplatin was injected using a 3 ml or 5 ml syringe in the opposite paw
from the study compound or saline. Recovery time from anaesthesia was 5 to
8 minutes.
Drug Preparation. Cisplatin bulk powder was weighed and dissolved in normal
saline at 75.degree. C. to provide a 5 mg/ml solution (90 mg was placed in
a scintillation vial and qs with 18 ml saline). The solution was stirred
and maintained at 40.degree. C. until ready for use. The study drug was
weighed and dissolved in normal saline at room temperature to provide a 1
mg/ml solution (10 mg was placed in a scintillation vial and qs with 10 ml
saline). Suspensions were heated to 40.degree. C. to bring the study
compound into solution. Compounds not soluble under these conditions were
not assayed.
Assay. Cisplatin was injected i.v. at 10 mg/kg into twelve anesthetized
ferrets daily at time zero. Normal saline (0.5 ml) or the study compound
(0.1 or 1.0 mg/kg) was injected 30 minutes later in groups of three
anesthetized ferrets. Order of treatment and treatment dose was selected
at random, with the remaining treatment dose assayed in the next
experiment.
Experimental Observations and Data Collection. Ferrets were viewed
individually. The time and number of emetic episodes were recorded for
four hours. Zero time was equivalent to the time of cisplatin injection.
An episode was defined as an expulsion of solids or liquid, or a retching
which resulted in an open mouth without expulsion. Retches were recorded
but not counted. The total number of episodes for each of the four groups
of three ferrets (+/-S.E.) was averaged and the effect of treatment (%
protection) was calculated as the percent reduction of emetic episodes
compared to controls.
##EQU1##
Percent protection values were determined from experimental controls.
Experimental controls were those obtained from the day of the experiment.
Onset times of the first episode were averaged and recorded for each
group. Prodromal signs (lip licking, slit eyes, head shaking, salivation,
scratching, clawing, walking backward, sedation, urination, and
defecation) were also averaged and recorded.
The compounds listed in Table 2 were tested by these procedures and found
to have the activities listed in the columns on the right side of Table 2.
In Table 2, 5-HT.sub.3, IC.sub.50, nM means the concentration of test
compound that displaces 50% of the radiolabelled ligand; ED.sub.50, mg/kg
means the median effective dose in terms of milligram per kilogram of body
weight, a dose that produces its effect in 50% of the population; % Prot,
0.1 mg/kg means the effect of treatment of 0.1 mg/kg dose of drug. For all
the compounds reported in Table 2 set out below, the IC.sub.50 value for
D.sub.2 receptor binding was>10,000 nm.
TABLE 2
__________________________________________________________________________
Pharmacological Data of 4,5,6,7-Tetrahydroimidazo[4,5-c]pyridinyl-6-carbox
ylic Acid Derivatives
##STR11##
Ferret Cisplatin Test
*C.sub.6 5-HT.sub.3 % Prot
Compd
Config.
R.sub.1
R.sub.2
R.sub.3
R.sub.4
R.sub.5
R.sub.6
R.sub.7 IC.sub.50, nM
ED.sub.50,
0.1
__________________________________________________________________________
mg/Kg
1 R H H H H H CH.sub.3
2-HOC.sub.6 H.sub.4 NH
10.9 0.063 73
2 R H H H H H CH.sub.3
5-Cl-2-CH.sub.3 OC.sub.6 H.sub.3 NH
10.02 0.4 31
3 R H H H H H CH.sub.3
2-CH.sub.3 OC.sub.6 H.sub.4 NH
47.63 2.08 9
4 R H H H H H CH.sub.3
2-COOCH.sub.3 C.sub.6 H.sub.4 NH
12.13 0.1 33
5 R H H H H H CH.sub.3
2-COCH.sub.3 C.sub.6 H.sub.4 NH
4.26 0.123 22
6 S H H H H H CH.sub.3
2-CH.sub.3 OC.sub.6 H.sub.4 NH
4.86 0.023 77
7 S H H H H H CH.sub.3
5-Cl-2-CH.sub.3 OC.sub.6 H.sub.3 NH
6.26 0.14 57
8 R H H H H H H 2-CH.sub.3 OC.sub.6 H.sub.4 NH
10.45 -- 62
9 R H H H H H CH.sub.3
C.sub.6 H.sub.5 NH
57.23 0.33 26
10 R H H H H H CH.sub.3
2-C.sub.2 H.sub.5 OC.sub.6 H.sub.4 NH
4.14 0.31 29
11 R H H H H H CH.sub.3
2-C.sub.6 H.sub.5 OC.sub.6 H.sub.4 NH
8.19 0.47 15
12 R H H H H H CH.sub.3
2-thiadizolyl-NH
273.46 40
13 R H H H H H CH.sub.3
2-benzothiazolyl-NH
71.52 0.074 76
14 S H H H H H H 2-CH.sub.3 OC.sub.6 H.sub.4 NH
8.53 0.062 48
15 S H H H H H CH.sub.3
2-HOC.sub.6 H.sub.4 NH
62.37 0.007 99
16 S H H H H H CH.sub.3
2-COOCH.sub.3 C.sub.6 H.sub.4 NH
29.03 0.01 42
17 S H H H H H CH.sub.3
2-C.sub.2 H.sub.5 OC.sub.6 H.sub.4 NH
15.37 0.2 58
18 S H H H H H C.sub.2 H.sub.5
2-HOC.sub.6 H.sub.4 NH
17.6 0.16 46
19 R H H H H H CH.sub.3
C.sub.6 H.sub.5 58.51 -- 8
20 S H H H CH.sub.3
CH.sub.3
CH.sub.3
2-CH.sub.3 OC.sub.6 H.sub.4 NH
21.69 0.008 72
21 R H H H H H CH.sub.3
4-[2,1,3-benzothiadiazol]yl-NH
1.98 0.39 24
22 S H H H H H CH.sub.3
2-benzothiazolyl-NH
37.18 -- 14
23 S H H H H H CH.sub.3
4-[2,1,3-benzothiadiazol]yl-NH
15.88 0.016 100
24 S H H H CH.sub.3
CH.sub.3
CH.sub.3
2-HOC.sub.6 H.sub.4 NH
47.2 0.025 48
25 S H H H CH.sub.3
CH.sub.3
CH.sub.3
2-CH.sub.3 OC.sub.6 H.sub.4 NH
14.05 0.026 93
26 S H H H H H CH.sub.3
2-C.sub.6 H.sub.5 C(O)NHC.sub.6 H.sub.4
289.14
-- 0
27 S H H H H H CH.sub.3
2-C.sub.6 H.sub.5 OC.sub.6 H.sub.4 NH
6.92 0.031 72
28 S H H H H H CH.sub.3
2-thienyl 647.79
-- 0
29 S H H H H H CH.sub.3
2-FC.sub.6 H.sub.4 NH
335.50
0.024 88
30 S H H H H H CH.sub.3
2,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3
69.73 -- 5
31 S H H H H H CH.sub.3
2,3-(F).sub.2 C.sub.6 H.sub.3 NH
643.79
0.068 91
32 S H H H H H CH.sub.3
2-benzo[b]thiophenyl
234.48
0.11 41
33 S H H H H H CH.sub.3
2-benzo[b]furanyl
2023.94
0.43 31
34 S H H H H H CH.sub.3
2,6-(F).sub.2 C.sub.6 H.sub.3 NH
611.88
0.15 59
35 S H H H H H CH.sub.3
2,3,4-(F).sub.3 C.sub.6 H.sub.2 NH
159.88
0.19 20
36 S H H H H H CH.sub.3
8-(1,2,3,4-tetrahydro-
102.84
0.081 70
quinolin)yl-NH
37 S H H H H H CH.sub.3
2-ClC.sub.6 H.sub.4 NH
26.74 0.065 42
38 S H H H H H CH.sub.3
C.sub.6 H.sub.5 48.45 -- 30
39 S H H H H H CH.sub.3
2-CH.sub.3 C(O)C.sub.6 H.sub.4 NH
4.18 0.045 65
40 S H H H H H CH.sub.3
2,5-(OH).sub.2 C.sub.6 H.sub.3 NH
45.92 -- 0
41 S H H H H H CH.sub.3
2-(5-(CH.sub.3 O)-benzo[b]furan)yl-
12881.17
-- 9
42 S H H H H H CH.sub.3
2-NH.sub.2 C.sub.6 H.sub.4 NH
3494.32
0.23 39
43 S H H H H H CH.sub.3
2-CH.sub.3 OC.sub.6 H.sub.4
2377.80
-- 41
44 S H H H H H CH.sub.3
2-(3-CF.sub.3 C.sub.6 H.sub.4 O)C.sub.6
H.sub.4 NH 9.52 0.26 1
45 S H H H H H CH.sub.3
2-(3-FC.sub.6 H.sub.4 O)C.sub.6 H.sub.4
7.09 0.042 67
46 S H H H H H CH.sub.3
2,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.4
162.26
-- 50
47 S H H H H H CH.sub.3 CO
2-CH.sub.3 OC.sub.6 H.sub.4 NH
-- 0.044 81
48 S H H H CH.sub.3
CH.sub.3
H 2-CH.sub.3 COC.sub.6 H.sub.4 NH
158.21
0.0098 100
49 S H H H CH.sub.3
CH.sub.3
H 2-C.sub.6 H.sub.5 OC.sub.6 H.sub.4 NH
8.55 0.022 76
50 Granisetron 1.05 0.030 71
51 Metaclopramide 514.00
4.08 17
52 Ondansetron 5.00 0.041 77
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While we have represented a number of embodiments of this invention, it is
apparent that the basic construction can be altered to provide other
embodiments which utilize the invention without departing from the spirit
and scope of the invention. All such modifications and variations are
intended to be included within the scope of the invention as defined in
the appended claims rather than the specific embodiments which have been
presented by way of example.
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